Essential Role of RelB in Germinal Center and Marginal Zone Formation and Proper Expression of Homing Chemokines

Abstract

High levels of the Rel/NF-κB family member RelB are restricted to specific regions of thymus, lymph nodes, and Peyer’s patches. In spleen, RelB is expressed in periarteriolar lymphatic sheaths, germinal centers (GCs), and the marginal zone (MZ). In this study, we report that RelB-deficient (relB−/−) mice, in contrast to nfkb1−/−, but similar to nfkb2−/− mice, are unable to form GCs and follicular dendritic cell networks upon Ag challenge in the spleen. RelB is also required for normal organization of the MZ and its population by macrophages and B cells. Reciprocal bone marrow transfers demonstrate that RelB expression in radiation-resistant stromal cells, but not in bone marrow-derived hemopoietic cells, is required for proper formation of GCs, follicular dendritic cell networks, and MZ structures. However, the generation of MZ B cells requires RelB in hemopoietic cells. Expression of TNF ligand/receptor family members is only moderately altered in relB−/− splenocytes. In contrast, expression of homing chemokines is strongly reduced in relB−/− spleen with particularly low mRNA levels of the chemokine B lymphocyte chemoattractant. Our data indicate that activation of p52-RelB heterodimers in stromal cells downstream of TNF/lymphotoxin is required for normal expression of homing chemokines and proper development of spleen microarchitecture.

The anti‐apoptotic factor Bcl‐2 can functionally substitute for the B cell survival but not for the marginal zone B cell differentiation activity of BAFF

“…RelB and p50, two subunits of the NF-‹ B transcription factor, are required for marginal zone B cell formation [37,38] and may mediate BAFF signaling in that respect.…”

NF-κB and the immune response

“…Mice deficient in the non-canonical pathway fail to segregate B-cell-T-cell zones and FDC networks, and they fail to form GCs following immunization. Marginal zone macrophages, which line the border between red and white pulp areas, are also absent or disorganized in RelB, p52, NIK or IKKa knockouts (Franzoso et al, 1998;Weih et al, 2001). Some splenic defects are also attributable to effects on hematopoietic cells.…”

Crosstalk via the NF-κB signaling system

“…Indeed, genetic analysis indicated that RelB plays an essential role in lymph node development, especially in maintaining lymph node architecture in adult mice (Weih et al, 2001;Yilmaz et al, 2003). Important lymphoid chemokine genes, such as BLC and SLC, were shown to be RelB target genes (Basak et al, 2008;Schneider et al, 2004) via a proposed variant kappaB site that recruits RelB-but not RelA-containing dimers upon LTβR stimulation (Bonizzi et al, 2004).…”